Thomas Ball is an Assistant Professor in the Department of Pediatrics at the University of Arizona. Dr. Ball is seeking support to focus his efforts on developing, through coursework and laboratory training, the knowledge and skills needed to pursue investigations into the hormonal influences on the genesis of allergic disease and asthma. The Arizona Respiratory Sciences Center (ARSC) is a multi-disciplinary environment with a long history of successful investigations into the epidemiology and etiology of childhood respiratory diseases. We recently found that children who were exposed to more children during infancy, a critical time in the maturation of the immune response, were at lower risk of subsequently developing atopy and asthma. This finding, along with other epidemiologic analyses, is consistent with the theory that improved hygiene in industrialized countries is responsible for the recent epidemic of asthma and allergic disease. It is speculated that bacterial endotoxin such as lipopolysaccharide (LPS), through binding with CD14, might mediate the molecular mechanisms underlying this "hygiene hypothesis," presumably by influencing T-helper (Th) cell development into Thl or Th2 type cells. However, endotoxin is also known to stimulate the hypothalamic-pituitary-adrenal axis (HPAA), which in turn leads to increased levels of endogenous cortisol. Cortisol is known to have not only protective effects on the lung, but also influence on T and B cell differentiation. Since testosterone, which is elevated in male infants, inhibits endotoxin stimulation of the HPAA this may explain why the recent asthma epidemic has affected boys more than girls. While much research has evaluated the effect of glucocorticoids on numerous immunologic pathways and mediators, little information exists regarding the net effect of endogenous cortisol on T and B cell differentiation early in life. We hypothesize that endotoxin increases endogenous cortisol through stimulation of the HPAA, which in turn protects the developing lung from inflammation and influences T cell differentiation early in life. This hypothesis will be addressed by accomplishing the following specific aims: 1) Elucidate the relationship between exposure to other children at day care and salivary cortisol levels; 2) Determine the relationship between salivary cortisol levels and the production of Thl-type and Th2-type cytokines by mononuclear cells in infancy; 3) Assess the role of the glucocorticoid receptor in the mechanism determining differential cytokine responses among infants with differing concentrations of salivary cortisol. Accomplishment of these aims will allow us to perform future studies that will elucidate the gene-environment interactions influencing the effect of the HPAA on the development of asthma and allergies.